This presentation will cover: 1) MOA-based smart strategies in making decisions about bispecific vs. combination mixtures; 2) novel bispecific strategies in maximizing the potential of combination biologics/targets through a single molecule; 3) smart engineering approaches to optimize valency, potency, avidity and half-life of bispecific IgG like mAbs; 4) minimize toxicity resulting from the simultaneous hit of two targets or redirected effector cells; 5) on and off-target toxicities and PK-PD resulting from the modulation of two targets should be carefully evaluated very early in drug development.

In the US, the bispecific T-cell engager (BiTE®) antibody construct blinatumomab has been approved for the treatment of relapsed or refractory B-precursor acute lymphoblastic leukemia and more recently, also in the respective minimal residual disease setting. This talk will focus on Amgen's subsequent BiTE® pipeline in various hematologic malignancies like acute myeloid leukemia and multiple myeloma but also in solid tumor indications.

2:30 Advances with Bispecifics and Multi-Specifics in the Clinic - Lessons Learned

Tariq Ghayur, PhD, Senior Research Fellow, AbbVie

Of the many bi-/multi-specific biologics formats reported to date, some have progressed to clinical and late preclinical stages. Two areas of focus are now: 1) developing approaches to identify/select targets and/or target pairs with "novel" biology that absolutely requires bi-/multi-specific format; i.e., the specific biology cannot be achieved with monoclonal antibody combinations, and 2) to select the right format to achieve desired outcomes.

Up-regulation of CD47 is an immune evasion mechanism used by different cancers to evade immune surveillance through the delivery of a universal "don't eat me" signal to phagocytes. In order to avoid poor pharmacological properties and potential hematological toxicities linked to the indiscriminate blockage of ubiquitously expressed CD47, we developed a bispecific antibody (NI-1801) capable of selectively inhibiting CD47 on mesothelin-positive tumor cells. Due to the specificity of a targeting approach, NI-1801 retains potent anti-cancer efficacy both in vitro and in vivo while showing favorable pharmacological and toxicology profiles.

Bispecific antibodies have distinct advantages over monospecific antibodies by enabling more specific targeting and novel mechanisms of action. We have used our B-Body™ bispecific antibody platform to create antibodies allowing for redirected T cell killing, SNIPER™ antibodies that specifically target subsets of cells for elimination, and antibodies with enhanced agonist activity. Using these antibodies, we show the advantages of being able to screen for functional activity in order to select for a desired response.

Carbohydrates on the surface of cancer cells represent preferable targets for bispecifics due to their unique tumor-specificity with lack or inaccessibility on normal tissues and broad indication coverage. In a platform approach, we designed and screened several T cell engaging bispecific constructs recognizing the highly tumor-specific carbohydrate/protein antigen TA-MUC1 and CD3 that differed in binding valencies and affinities towards both antigens, serum half-life, molecule size, and Fc-functionality and produced them in our human expression platform GlycoExpress®.

Xencor has applied its XmAb bispecific technology platform to create multiple novel modalities for T cell derepression and activation. These include dual checkpoint inhibitors such as a PD1 x CTLA4 bispecific antibody, and a CTLA4 x LAG3 bispecific antibody that combines productively with anti-PD1 for triple checkpoint blockade. We have also discovered a highly active PD1 x ICOS bispecific antibody that productively combines checkpoint blockade and costimulation into a single molecule. Finally, we have utilized our heterodimeric Fc domain to create a novel long-acting IL15/IL15Ra-Fc format for immunotherapy.

2:15 FEATURED PRESENTATION: Mechanisms of Action for the Application of BiTE Antibodies in Immunotherapy Combinations

This presentation will cover: 1) role of costimulatory pathways in T cell biology; 2) rationale for tumor localized activation of costimulatory receptors; 3) case study: in vitro and in vivo characterization of the HER2/4-1BB bispecific molecule PRS-343.

CD3 bispecific antibodies induce rapid activation of T cells leading to degranulation of cytolytic vesicles and apoptosis of target expressing cancer cells. T cell activation results also in feedback inhibition. PD1 up regulation has been described with multiple molecules and shown to inhibit activity of CD3 bispecific antibodies. The role of other co-inhibitory molecules is less clear. Our goal is to systematically characterize induction and functional role of key co-inhibitory and co-stimulatory molecules upon treatment with CD3 bispecific antibodies to identify optimal combination strategies.

Informed by successes achieved using immunotherapeutic approaches including checkpoint inhibitors and CAR T cells, tremendous attention has now focused on further harnessing the inherent power of the immune system to treat cancer using various combination regimens. A diverse range of pathways provide positive and negative signals to regulate the overall function of T cells. To simultaneously target these pathways, antibody combinations have been tested and demonstrated encouraging clinical activity in patients treated with Anti-PD-1 antibodies in combination with antibodies targeting CTLA-4 or LAG-3.

Combination immunotherapies can more effectively control tumors compared to monotherapies, but also have greater potential to elicit adverse events. We developed OrthomAb, a novel combinatorial single-drug biologic comprised of mAb agonists to the TNFR family costimulatory receptors CD134 and CD137 covalently-linked into a heterodimer, that potentiates T cell effector functions and in vivo tumor control. Importantly, OrthomAb's tetravalent structure should enable the minimization of adverse events while preserving therapeutic efficacy.